This application requests support for continuation of a highly productive scientific collaboration between Stanford University, The Salk Institute and other affiliated sites participating in this program project. Since the transfer of Project III to Stanford during the third year of the current project period, significant period, significant progress has been made in characterizing neuromorphological variation of the brain in WMS. In particular, analyses of structural neuroimaging data that, compared to normal controls, individuals with WMS have a unique profile of neuroanatomical variations with predisposition for particular volume and shape abnormalities. These include (1) reduced volume of posterior cerebral regions, (2) disproportionately reduced cerebral white matter volume, (3) disproportionately increased size of the cerebellum (including posterior vermis), superior temporal gyrus, right amygdala and superior temporal gyrus, and (4) abnormal cerebral and callosal shape as shown by 2D "bending angle" analysis. Further, pilot fMRI studies in four subjects confirm the feasibility of using this imaging modality in the WMS population and suggest that aberrant brain activation occurs in this condition. In view of these findings, new imaging studies are proposed to further explicate the neuroanatomical and neurofunctional profiles associated with WMS. These studies will elucidate, more precisely, the nature of variations in volume, shape and white matter integrity/connectivity of the WMS brain. Utilizing functional MRI, we also will directly investigate neural pathways underlying the WMS neurocognitive phenotype. The proposed imaging studies of WMS, within the context of this program project, provide an exceptional opportunity to examine critical associations among measures of cognition and behavior, neuroanatomy and brain function, and genetic influences. The results of this research, and their interpretation in parallel with related genetic, neurocognitive, neuropathological and electrophysiological data holds promise to reveal critical insights into bridging cognition and gene in WMS.